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(Circulation. 2005;111:222-229.)
© 2005 American Heart Association, Inc.

Transplantation

KRP-203, a Novel Synthetic Immunosuppressant, Prolongs Graft Survival and Attenuates Chronic Rejection in Rat Skin and Heart Allografts

Hisashi Shimizu, MD; Masafumi Takahashi, MD, PhD; Takashi Kaneko, MD, PhD; Takashi Murakami, MD, PhD; Yoji Hakamata, DVM, PhD; Shinji Kudou, BSc; Tetsuya Kishi, BSc; Kazunori Fukuchi, MSc; Satoru Iwanami, MSc; Kazuhiko Kuriyama, MSc; Tokutaro Yasue, MSc; Shin Enosawa, MD, PhD; Koshi Matsumoto, MD, PhD; Izumi Takeyoshi, MD, PhD; Yasuo Morishita, MD, PhD; Eiji Kobayashi, MD, PhD

From the Division of Organ Replacement Research (H.S., M.T., T.K., T.M., Y.H., E.K.), the Center for Molecular Medicine, Jichi Medical School, Tochigi, Second Department of Surgery (H.S., I.T., Y.M.), Gunma University, School of Medicine, Gunma, Department of Organ Regeneration (M.T.), Shinshu University, Graduate School of Medicine, Matsumoto, Discovery Research Laboratories (S.K., T.K., K.F., S.I., K.K., T.Y.), Kyorin Pharmaceutical Co, Ltd, Tochigi, Department of Regeneration Surgery (S.E.), and the National Research Institute for Child Health and Development, Tokyo, Division of Pathology (K.M.), Second Hospital of Nippon Medical School, Kanagawa, Japan.

Correspondence to Masafumi Takahashi, MD, PhD, Division of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical School, Minamikawachi-machi, Tochigi 329-0498, Japan. E-mail masafumi{at}jichi.ac.jp

Received July 31, 2004; revision received September 26, 2004; accepted September 30, 2004.

Background— A novel immunomodulator, KRP-203, the molecular structure of which has some similarity to FTY720, has been developed for use in organ transplantation. The present study was designed to investigate the potency and safety of KRP-203 on allograft survival against both acute and chronic rejection in rat skin and heart transplantation.

Methods and Results— KRP-203 significantly prolonged skin or heart allograft survival of a minor histocompatibility complex (mHC)–disparate (LEW to F344) rat combination. Histopathological and immunohistochemical analysis at 100 days after mHC-disparate rat heart transplantation revealed that KRP-203 treatment significantly inhibited infiltration of inflammatory cells, including macrophages and T cells; expression of endothelin-1 and transforming growth factor-ß₁; and IgG deposition and eventually attenuated neointimal formation and myocardial fibrosis. KRP-203 also prolonged heart allograft survival in a major histocompatibility complex (MHC)-incompatible (DA to LEW) rat combination, but the efficacy was not as significant. However, KRP-203 combined with a subtherapeutic dose of cyclosporin A synergistically prolonged the heart allograft survival. Flow cytometric analysis demonstrated that KRP-203 reduced the number of peripheral blood mononuclear cells (lymphocytes and monocytes) but not granulocytes and enhanced lymphocyte homing into peripheral lymph nodes. The influence of KRP-203 on heart rate changes in Hartley guinea pigs was examined. KRP-203 had less of a tendency to cause bradycardia than FTY720.

Conclusions— These findings demonstrated that KRP-203 prolonged skin and heart allograft survival and significantly attenuated chronic rejection and bradycardia as an adverse effect. Therefore, KRP-203 offers considerable potential as a novel therapeutic immunosuppressant in patients with organ transplantation.

Key Words: arteriosclerosis • rejection • transplantation • heart rate

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